Cancer is characterized by rampant genetic and epigenetic alterations. Recurrent DNA copy number alterations often indicate the presence of key drivers of cancer in the affected loci. Metadherin (MTDH; also called AEG1, LYRIC) has previously been identified as a pro-metastasis gene that resides in 8q22, a frequently amplified genomic locus linked to poor relapse-free survival of breast cancer (Hu et al., 2009). Overexpression of MTDH is observed in more than 40% of primary tumors and is an independent poor-prognosis factor (Hu et al., 2009). What drives the strong selection of MTDH in primary breast tumors is unclear and the functional significance of MTDH in normal development and tumorigenesis remains poorly understood.
Recent studies using cell culture or xenograft models have implicated MTDH in several cancer-related processes, including proliferation, cell death, invasion, and angiogenesis (Emdad et al., 2013), although the underlying mechanistic understanding of MTDH in these processes remains limited to date. In breast cancer, MTDH was postulated to be a transmembrane protein that mediates the adhesion of cancer cells to the lung endothelium (Brown and Ruoslahti, 2004). In certain cancer types, MTDH has been linked to multiple oncogenic pathways such as PI3K/AKT and NF-κB (Emdad et al., 2013). How MTDH regulates these pathways remains elusive. Although evolutionarily conserved in higher vertebrates, MTDH contains no recognizable functional domain, rendering the understanding of its biological function challenging. Multiple groups have identified several MTDH-binding partners, including PLZF, BCCIPα and Staphylococcal nuclease domain-containing 1 (SND1) (Wan and Kang, 2013). However, whether and how the interactions with these proteins mediate the function of MTDH is largely unknown.
Breast cancer is a heterogeneous disease that can be broadly classified into luminal and basal-like subtypes based on gene expression profiles (Perou et al., 2000). It has been speculated that different oncogenic signaling may target different cells of origin, thus leading to the formation of different subtypes of breast cancer. However, the origin, identity and regulation of tumor-initiating cells (TICs) in different oncogene-induced mammary tumors remain poorly characterized. Autochthonous tumorigenesis in mice offers great models for tracking the early changes during tumor initiation and for investigating the role of a gene of interest in mediating the transformation and expansion of TICs.